This project uses an approach integrating epidemiologic and laboratory methods to measure genetic damage and alterations in metabolism associated with human exposures to toxic chemicals. Laboratory tests for measuring genetic damage include assays for modifications at each of the three levels of organization of genetic material: chromosomal, gene or specific locus, and chemical. Tests for measuring alterations in metabolism include enzymatic and immunological assays for the activity of mono-oxygenase enzymes in human tissues and blood cells. Newly developed assays are initially used to study subjects with large, precisely defined exposures (e.g. medical exposure to cytotoxic drugs); if the assays prove sufficiently sensitive they are then used to study subjects with less intense and less well characterized exposures (e.g. occupational, lifestyle, and other environmental exposures). Groups under study include patients and workers exposed to cytotoxic drugs, individuals exposed to active and passive smoking, women accidentally exposed to large quantities of PCBs and their offspring, and children exposed to lead. The project emphasizes interdisciplinary development of study approaches with attention to details of both the laboratory procedures and the gathering and analysis of data concerning human subjects. These studies are designed to help evaluate and refine approaches that can be used to investigate both mechanisms involved in the etiology of cancer and other chronic diseases and effects of exposures that may be important to public health.